» Articles » PMID: 18160661

Modifying L-type Calcium Current Kinetics: Consequences for Cardiac Excitation and Arrhythmia Dynamics

Overview
Journal Biophys J
Publisher Cell Press
Specialty Biophysics
Date 2007 Dec 28
PMID 18160661
Citations 52
Authors
Affiliations
Soon will be listed here.
Abstract

The L-type Ca current (I(Ca,L)), essential for normal cardiac function, also regulates dynamic action potential (AP) properties that promote ventricular fibrillation. Blocking I(Ca,L) can prevent ventricular fibrillation, but only at levels suppressing contractility. We speculated that, instead of blocking I(Ca,L), modifying its shape by altering kinetic features could produce equivalent anti-fibrillatory effects without depressing contractility. To test this concept experimentally, we overexpressed a mutant Ca-insensitive calmodulin (CaM(1234)) in rabbit ventricular myocytes to inhibit Ca-dependent I(Ca,L) inactivation, combined with the ATP-sensitive K current agonist pinacidil or I(Ca,L) blocker verapamil to maintain AP duration (APD) near control levels. Cell shortening was enhanced in pinacidil-treated myocytes, but depressed in verapamil-treated myocytes. Both combinations flattened APD restitution slope and prevented APD alternans, similar to I(Ca,L) blockade. To predict the arrhythmogenic consequences, we simulated the cellular effects using a new AP model, which reproduced flattening of APD restitution slope and prevention of APD/Ca(i) transient alternans but maintained a normal Ca(i) transient. In simulated two-dimensional cardiac tissue, these changes prevented the arrhythmogenic spatially discordant APD/Ca(i) transient alternans and spiral wave breakup. These findings provide a proof-of-concept test that I(Ca,L) can be targeted to increase dynamic wave stability without depressing contractility, which may have promise as an antifibrillatory strategy.

Citing Articles

Bacterial toxins and heart function: heat-labile enterotoxin B promotes changes in cardiac function with possible relevance for sudden cardiac death.

Ferreira G, Cardozo R, Sastre S, Costa C, Santander A, Chavarria L Biophys Rev. 2023; 15(4):447-473.

PMID: 37681088 PMC: 10480140. DOI: 10.1007/s12551-023-01100-6.


Palmitoylation of the pore-forming subunit of Ca(v)1.2 controls channel voltage sensitivity and calcium transients in cardiac myocytes.

Kuo C, Dobi S, Gok C, Da Silva Costa A, Main A, Robertson-Gray O Proc Natl Acad Sci U S A. 2023; 120(7):e2207887120.

PMID: 36745790 PMC: 9963536. DOI: 10.1073/pnas.2207887120.


Models of the cardiac L-type calcium current: A quantitative review.

Agrawal A, Wang K, Polonchuk L, Cooper J, Hendrix M, Gavaghan D WIREs Mech Dis. 2022; 15(1):e1581.

PMID: 36028219 PMC: 10078428. DOI: 10.1002/wsbm.1581.


L-type channel inactivation balances the increased peak calcium current due to absence of Rad in cardiomyocytes.

Ahern B, Sebastian A, Levitan B, Goh J, Andres D, Satin J J Gen Physiol. 2021; 153(9).

PMID: 34269819 PMC: 8289690. DOI: 10.1085/jgp.202012854.


The transient outward potassium current plays a key role in spiral wave breakup in ventricular tissue.

Landaw J, Yuan X, Chen P, Qu Z Am J Physiol Heart Circ Physiol. 2021; 320(2):H826-H837.

PMID: 33385322 PMC: 8082802. DOI: 10.1152/ajpheart.00608.2020.


References
1.
Arena J, Kass R . Activation of ATP-sensitive K channels in heart cells by pinacidil: dependence on ATP. Am J Physiol. 1989; 257(6 Pt 2):H2092-6. DOI: 10.1152/ajpheart.1989.257.6.H2092. View

2.
Mahajan A, Shiferaw Y, Sato D, Baher A, Olcese R, Xie L . A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates. Biophys J. 2007; 94(2):392-410. PMC: 2157228. DOI: 10.1529/biophysj.106.98160. View

3.
Goldhaber J, Parker J, Weiss J . Mechanisms of excitation-contraction coupling failure during metabolic inhibition in guinea-pig ventricular myocytes. J Physiol. 1991; 443:371-86. PMC: 1179846. DOI: 10.1113/jphysiol.1991.sp018838. View

4.
Bassani J, Yuan W, Bers D . Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol. 1995; 268(5 Pt 1):C1313-9. DOI: 10.1152/ajpcell.1995.268.5.C1313. View

5.
Shaw R, Rudy Y . Electrophysiologic effects of acute myocardial ischemia. A mechanistic investigation of action potential conduction and conduction failure. Circ Res. 1997; 80(1):124-38. DOI: 10.1161/01.res.80.1.124. View